tbuckley/cabot-search huggingface dataset:
Abstract 15540: Single Cell Transcriptional-Epigenetic Profiling and Sub-Cellular Proteomics Demonstrate That HIV-Nef Extracellular Vesicles Modulate Human Macrophage Heterogeneity to Promote Atherosclerosis
Authors: Sarvesh Chelvanambi, Julius Decano, Rile Ge, Yoshihiro Yanagihara, Mary Whelan, Amelie Jule, Shiori Kuraoka, Shin Mukai, Takashi Enomoto, Jonas Zimmer, Francesca Bartoli-Leonard, Abhijeet Sonawane, Takeshi Tanaka, Diego V Santinelli-Pestana, Taku Kasai, Tan Pham, Joan T. Matamalas, Shannan Ho Sui, Elena Aikawa, Sasha A Singh, Masanori Aikawa
Journal: Circulation (2022)

Background: In the era of modern Anti-Retroviral Therapy, people living with HIV continue to remain at a higher risk than the general population for cardiovascular diseases including atherosclerosis. We hypothesized that circulating extracellular vesicles (EV) containing HIV-Nef protein promote inflammation by switching the pattern of macrophage heterogeneity towards a pro-inflammatory state that underlies cardiovascular disease. Methods &amp; Results: Human primary macrophages were stimulated with EV engineered to contain HIV-Nef. Macrophage heterogeneity was characterized by simultaneous single cell mRNA-seq and single cell ATAC-seq integrated with WNN mapping in 50,931 cells. Among 16 clusters (Fig. A), pseudotime (Slingshot), gene regulatory (DoRothEA and SCENIC) and transcription factor motif accessibility (ChromVar) analyses demonstrated that HIV-Nef regulates 3 inflammatory clusters as gauged by differentially active and accessible transcription factors, e.g., JUN, YY1 and STAT1. Sub-cellular proteomics identified differentially abundant proteins associated with DNA (662 proteins), nucleus (261), cytosol (461), cell surface (72) and EV (132). Pathway enrichment analysis of these proteins revealed changes in biological processes in immune responses, cytoskeletal regulation, and metabolism. Functional phenotyping showed HIV-Nef shifts macrophages towards a pro-inflammatory phenotype by suppressing atheroprotective efferocytosis, promoting chemotaxis and altering metabolic state. Furthermore, short-term injection of HIV-Nef EV into WT mice induced inflammatory chemokine secretion, while long-term injection into Ldlr -/- mice enhanced atherogenesis (Fig.B). Conclusions: Persistent Nef in EV of HIV survivors may modulate macrophage heterogeneity to promote chronic inflammation. These findings may help identify patients at risk for cardiovascular complications and develop novel atheroprotective therapies.
Abstract 15427: Reduction of Epicardial Fat, Clinical Risk Factors &amp; Symptomatology in Paroxysmal AF Patient With Severe Aortic Stenosis and Metabolic Syndrome via Mobile Cardiometabolic Health &amp; Weight Loss Program
Authors: Jessica Barnes, Gerald Dembrowski, Srikanth Vallurupalli, Abdallah Malkawi, Subodh Devabhaktuni, Hakan Paydak, Julius Balogh, John Mounsey
Journal: Circulation (2022)

Atrial fibrillation (AF) is dependent on epicardial fat (EpF) accumulation and infiltration. Complementary therapeutic strategies specifically targeting EpF present an opportunity for slowing progression and reversing the course of AF. A 73-year-old man with a history paroxysmal AF (managed by rate control/anticoagulation), severe aortic valve stenosis (AVS, area 1cm 2 , EF 55%), controlled hypertension, diabetes, and obesity (BMI 37.9) completed a 2-month cardiometabolic health program (CHP). The ‘tech plus touch’ CHP, delivered via a smartphone, utilized a comprehensive approach with physiological, nutritional, and behavioral components. Along with patented dietary regimens and nutritional supplementation implemented with personalized treatment algorithms, the CHP included direct daily engagement (messaging &amp; telehealth) with a staff clinician via the HIPAA compliant mobile app. Patient data visible to both the patient and staff clinician was synced automatically via Bluetooth-linked devices. EpF dropped by 25.5% over 9w (transthoracic echo, Fig1). BMI, visceral adiposity, and body fat were significant reduced, while lean body mass (LBM), muscle mass (MM) and intracellular fluid (ICF, a validated surrogate of chronic inflammation) improved (Fig1). Encouragingly, LBM, MM, and ICF improvements were unusual and particularly large in this older, physically inactive patient. Other clinical risk factors improved including diabetes, kidney function and inflammation. The patient reported resolution of chest pain and dyspnea, improved cardiorespiratory fitness, and began aerobic exercise. Our data demonstrate a nonpharmacologic complementary approach produces significant reductions of EpF and modifiable risk factors linked to hypertension, diabetes, and chronic inflammation in an AF patient with AVS and metabolic syndrome. Whether this will lead to a reduction in AF burden or conversion to persistent AF, remains to be determined.
Abstract 15710: Point-of-Care Ultrasonography: Artificial Intelligence in the Assessment of Left Ventricular Function
Authors: Pouya Motazedian, Jeffrey Marbach, Graeme Prosperi-Porta, Simon Parlow, Pietro Di Santo, Richard Jung, Omar Abdel-Razek, William Bradford, Miranda Tsang, Michael Hyon, Stefano Pacifici, Sharanya Mohanty, Gordon S Huggins, Trevor Simard, Benjamin M Hibbert
Journal: Circulation (2022)

Introduction: Point-of-care ultrasonography (PoCUS) has become routine for the bedside assessment of patients. Current evidence shows that image acquisition and interpretation of left ventricular function can be achieved reliably by trained users, but evidence is lacking for interpretation by artificial intelligence. We sought to evaluate the accuracy of PoCUS devices with integrated artificial intelligence in comparison to transthoracic echocardiograms for assessment of left ventricular ejection fraction (LVEF). Methods: This is a prospective, multicenter cohort study using the KOSMOS portable ultrasound device (EchoNous, Redmon, WA). PoCUS studies included an apical four and two chamber views and were obtained by either novice trainees or experienced ultrasonographers. A real-time, automated LVEF was calculated by the device using a modified Simpson’s method. These patients also underwent a formal transthoracic echocardiogram, with image acquisition and interpretation completed by blinded ultrasonographers and level-3 trained echocardiographers, respectively. Results: A total of 449 patients were enrolled in the study with 227 and 222 studies completed by novice and experienced scanners, respectively. Images of suitable quality were obtained in 208 of the novice cohort (91.6%) and 216 of the experienced cohort (97.3%). In comparison to formal echocardiography, linear regression shows a R 2 value of 0.82 for the total cohort, and 0.85 for the novice and 0.72 in experienced scanner subgroups. Incorporating an intra-observer variability of ± 5%, the sensitivity and specificity for an abnormal (≤50%) and severely reduced (≤30%) LVEF was 99.2% and 97.7%, and 86.8% and 99%, respectively. Conclusions: Our study is one first to assess the accuracy of PoCUS devices with integrated artificial intelligence. Based on our study, a real-time, automated LVEF can be acquired by PoCUS with strong correlation to formal echocardiography. This study also highlights that diagnostic quality studies can be acquired by novice scanners with comparable accuracy to experienced scanners. This provides evidence for an immediate and inexpensive method for accurate LVEF assessment in emergent and resource-limited environments.
Abstract 15440: Elevated Serum Transthyretin Concentration Found to be Associated With Increased Survival Rate in Hereditary Transthyretin Cardiomyopathy Patients
Authors: Dhanish Revanth Rangaswamy Nandakumar, Austin Rim, Rebecca Steinberg, Sreeram Yalamanchili, Rahul Patel, Matthew T Brown, Kunal Bhatt
Journal: Circulation (2022)

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) results from abnormal deposition of misfolded transthyretin (TTR) deposition in the myocardium. Prior studies have shown an association between lower serum concentrations of TTR with increased mortality in patients with wild-type TTR, suggesting that greater deposition of TTR from the blood into surrounding tissues may reflect increased disease severity. Hypothesis: Serum TTR levels are associated with mortality and HF hospitalization in hATTR patients with Val142Ile mutation. Methods: We conducted a retrospective chart review of patients diagnosed with hATTR-CM at Emory University's Cardiac Amyloidosis Clinic between January 2014 and April 2022 (n=65) and evaluated the association of serum TTR concentration with 1 year survival and 1 year HF hospitalization. We stratified patients on two TTR cut-offs: 18 mg/dL, based on a previous study in a wild-type cohort, and 14.9 mg/dL, the median TTR level in this cohort. Kaplan Meier Survival analysis and Cox proportional hazard modeling examined the association between serum TTR, overall survival, and HF hospitalization, adjusted for troponin-I, age, BMI, BNP, GFR and NYHA class as covariates. Results: Increased serum concentrations of TTR were significantly associated with decreased mortality within 1 year of diagnosis in multivariable models. Adjusted models showed a significant difference between the groups at both cut-offs only when the event was death within 1 year of diagnosis (Cutoff 14.9: HR = 14.02, 95% CI 2.4 - 82.5; cutoff 18: HR 367, 95% CI 35.24-3822.57), but no significant difference for the outcome of HF hospitalization at either cutoff point ( Table ). Conclusions: In our cohort of 65 hATTR patients with the Val142Ile mutation, lower TTR levels at the time of diagnosis were significantly associated with death at 1 year of diagnosis. TTR levels were not significantly associated with HF hospitalization within 1 year of diagnosis.
Abstract 265: Social Determinants Of Health Impact Phenotype-based Outcome Prediction After Pediatric Arrest
Authors: Ericka L Fink, Patrick M Kochanek, Ashok Panigrahy, Sue Beers, Rachel Berger, HULYA BAYIR, Chunyan Wang, Jose Pineda, Alexis A Topjian, aline maddux, Frederick Willyerd, Elizabeth A Hunt, Melissa G Chung, Christopher Newth, Lincoln Smith, Lesley Doughty, J Wesley Diddle, Juan Piantino, Karen H Walson, Binod Balakrishnan, stuart friess, Ashley Siems, Craig Press, Jason Patregnani, Michael T Meyer, Tamara Haller, Amery Treble-Barna, Robert Clark, Anthony Fabio
Journal: Circulation (2022)

The Personalizing Outcomes after Child Cardiac Arrest-1 (POCCA-1) trial showed that blood-based brain injury biomarkers have promise to prognosticate outcome post-pediatric cardiac arrest. However, whether POCCA-1 biomarkers perform accurately among all children is unknown. Hypothesis We hypothesized that POCCA-1 biomarkers will have different performance accuracy by distinct clinical phenotypes after pediatric cardiac arrest. Methods: Fourteen US centers enrolled 164 children aged &lt; 18 y with pediatric intensive care unit admission post-arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1, neurofilament light, and Tau proteins were measured in blood post-arrest d1-3. Patient ZIP codes linked to US census data provided socioeconomic neighborhood characteristics. We analyzed 120 children with evaluable data (n=50, unfavorable outcome [Vineland Adaptive Behavioral Scale &lt; 70 or dead]) to create 3 clinical phenotypes using latent class analysis. POCCA-1 biomarker levels and outcomes were analyzed by phenotype. The POCCA-1 model was analyzed to predict 1 y unfavorable outcome using multivariate AUROC by phenotype for all 4 biomarkers on d1- 3 post-arrest. Results: Group 1 (n=35, 22%) were older, of White race, with private insurance and out-of-hospital cardiac arrests (OOHCA), fewer fever post-arrest, living in neighborhoods of mostly White race and lower poverty. Group 2 patients (n=77, 47%) were younger, of White race, with in-hospital cardiac arrests living in more socioeconomically diverse neighborhoods. Group 3 (n=51, 31%) were diverse in race and age, of more male sex, with Medicaid insurance and asphyxial, OOHCA, living in more impoverished neighborhoods. Unfavorable outcome was higher in Group 3 (69%) vs 1 (48%) and 2 (28%), p&lt;0.001. All biomarkers (except Tau) were significantly increased on d1-3 in Group 3. Biomarker accuracy to predict outcome was excellent for Group 1 with 11/12 AUROCs significant. Models were less accurate for Group 2 (7/12) and marginal for Group 3 (3/12). Conclusions: The POCCA-1 prediction model performance varied by patient, arrest, and neighborhood context, suggesting that prediction models need to be personalized using clinically relevant and equitable phenotypes.
Abstract 15512: The Hepatic Lipid Type and Content Had an Impact on Hepatic Inflammation and Fibrosis in Streptozotocin-Induced Diabetic Mice
Authors: Masahiro Koseki, Jiuyang Chang, Ayami Saga, Kotaro Kanno, Katsunao Tanaka, Takashi Omatsu, Takeshi Okada, Hiroyasu Inui, Tohru Ohama, Makoto Nishida, Yasushi Sakata
Journal: Circulation (2022)

Introduction: It has been reported that nonalcoholic fatty liver disease is an independent risk factor for cardiovascular diseases. We have recently demonstrated that diet-induced steatohepatitis was associated with cardiac dysfunction and those were improved by the selective PPARα modulator, pemafibrate in wild type mice. Hypothesis: The aim of the study is to characterize the relationship between hepatic lipid content and inflammation, induced by two type of diets in diabetic mice model and to test the effect of pemafibrate on those. Methods: C57BL/6 mice were injected with streptozotocin (STZ) (40mg/kg for 4 days). Mice whose ad libitum blood glucose were 200-350mg/dl, were used as diabetic mice. In 11-week-old STZ induced diabetic mice were administered wild high fat/high cholesterol diet (WD group) or high fat/high cholesterol/ high sucrose/bile acids diet (NASH group), with or without pemafibrate for 12 weeks. Lipid profiles, liver cytokines, hepatic mRNA, liver histology were investigated. Results: Total cholesterol and unesterified cholesterol were significantly more accumulated in the NASH group compared to the WD group. Triglyceride were not changed between two groups. F4/80 positive area and sirius-red positive area were significantly increased in the NASH group compared to the WD group. Inflammatory cytokines such as Tnfa, Il1b and fibrosis associated genes Col1a1 and Col1a2 were also significantly increased in the NASH group, suggesting the presence of active inflammation and fibrosis in the NASH group. By co-administration with pemafibrate, serum HDL-C level was increased by 48.7% and the non-HDL-C level was decreased by 31.4% in the NASH/pemafibrate group. Importantly, total cholesterol and unesterified cholesterol were markedly decreased in the NASH/pemafibrate group. Along with those, F4/80 positive area and sirius-red positive area were decreased in the NASH/pemafibrate group by more than 50%. Hepatic Tnfa expression was decreased by 56.3% and Tgfb, Col1a1, Col1a2 was significantly decreased. Conclusions: Our study demonstrated that more total cholesterol and unesterified accumulation induced hepatic inflammatory responses and fibrosis in the diabetic mice and pemafibrate had the beneficial impacts on those.
Abstract 15530: Renal Outer Medullary Potassium (Kir 1.1) is not the Kir Subunit of a Cardioprotective, Diazoxide - Mediated Mitochondrial Adenosine Triphosphate - Sensitive Potassium Channel
Authors: Jie Wang, Janelle Sangalang, Kyriakos Papanicolaou, Benjamin Salazar, Sari Holmes, Brian Orourke, Jennifer S Lawton
Journal: Circulation (2022)

Objective: The adenosine triphosphate-sensitive potassium (K ATP ) channel opener diazoxide (DZX) mimics ischemic preconditioning and is cardioprotective. The molecular mechanism of action is unknown, although several mitochondrial candidate protein targets have been proposed. We suggested that cardioprotection occurs at a non-sarcolemmal channel, requires the inhibition of succinate dehydrogenase, and involves K ATP channel subunit SUR1. The renal outer medullary potassium channel (ROMK, or Kir1.1) subunit was proposed as the Kir subunit of a mitochondrial (m)K ATP channel. We tested the hypothesis that genetic deletion of ROMK will result in loss of DZX cardioprotection in a model of prolonged ischemia with cardioplegia. Methods: Mice lacking ROMK in cardiac myocytes (cKO) and wild-type (WT) litter mates were randomly assigned to 90 min. global ischemia in a Langendorff model following hypothermic hyperkalemic cardioplegia (CPG) or CPG + DZX (100 μM/L) (N=6-9 per group). Left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and coronary flow were compared before and after global ischemia. Data acquisition and interpretation were blinded to group. Results: Similar to previous results, prolonged global ischemia was associated with a reduction in LVDP and an increase in EDP with CPG that was prevented by DZX in WT. Unexpectedly, ROMK (cKO) mice were equally responsive to DZX (Figure), indicating that DZX protection is not mediated by ROMK channels. Conclusions: Genetic deletion of ROMK in cardiac myocytes does not negate cardioprotection provided by DZX, indicating ROMK is not a subunit of a cardioprotective mK ATP channel. Alternate proposed DZX-sensitive target channels or mechanisms of action remain to be tested. Identification of the specific subunits of a mK ATP channel would allow for targeted pharmacologic therapy to reduce myocardial stunning following prolonged ischemia, similar to that seen following cardiac surgery.
Abstract 15339: Er-Resident S1pr1 in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury
Authors: Mumtaz Anwar, Vijay Avin Balaji Ragunathrao, Mohammad Tauseef, Jagdish Chandra C Joshi, Rayees R Sheikh, Bhagwati Joshi, Yoshikazu Tsukasaki, Konstantinos Chronis, Dolly Mehta
Journal: Circulation (2022)

Endothelial-cell surface localized sphingosine 1 phosphate receptor 1 (S1PR1) is known to promote anti-inflammatory and barrier enhancing niche upon ligating S1P. Recently we showed that S1P and TNFα, later being a well-known inflammatory agonist, phosphorylate S1PR1 at tyrosine 143 (Y 143 ) which functions as an endoplasmic reticulum (ER) import signal (Anwar et al, 2021). ER-retained S1PR1 instructs barrier disruptive signaling but the mechanism remains unclear. Here, we generated S1PR1 knock-in mice using CRISPR-Cas9 strategy to edit endogenous S1PR1 into Y 143 D-S1PR1 (phospho mimicking) or Y 143 F-S1PR1 (phosphodefective) to test the hypothesis that ER-localized S1PR1 subverts EC from anti-inflammatory to pro-inflammatory EC leading to vascular injury. Because EC constitutes about 50% of cells in the lungs, we assessed if knock-in of Y 143 D-S1PR1 impaired lung homeostasis. We show that editing of S1PR1 into Y 143 D- or Y 143 F-S1PR1 did not alter total S1PR1 expression. Interestingly, Y 143 D-S1PR1 knock-in mice showed marked vascular leak at homeostasis along with increased neutrophil influx and inflammatory cytokine generation including TNFα, IL1ß and MiP2 as compared to Y 143 F-S1PR1 or WT mice. We next challenge these mice with intratracheal LPS. LPS-induced non-resolvable vascular inflammatory injury in Y 143 D-S1PR1 mice. Surprisingly, Y 143 F-S1PR1 knock-in mice did not develop vascular inflammatory injury. Furthermore, NFκB activity, a predominant transcription factor inducing inflammatory EC phenotype, was increased in EC transducing Y 143 D-S1PR1 mutant as compared to WT. However, TNFα failed to induce NFkB activity in EC transducing Y 143 F-S1PR1 mutant. Together, these results show that ER-resident S1PR1 program endothelial niche into immune-active niche by activating NFkB pathway leading to irreparable lung injury. Further experiments are being done to assess epigenetic changes (ATACseq and ChIP-Seq) in EC to address the concept the ER-resident S1PR1 controls the fate of immune cells in the lungs. We believe that understanding how ER-resident S1PR1 programs EC into inflammatory phenotype would allow development of new targets for treating the inflammatory vascular diseases including lung injury, ARDS, and COVID-19
Abstract 154: Limitation of Troponin T In Identifying the Cause of Out-of-hospital Cardiac Arrest
Authors: Bas J Verkaik, Paul Dekkers, Ton Slagboom, Christian van der Werf, Jorrit Lemkes, Rudolph W Koster
Journal: Circulation (2022)

Introduction: High Sense-Troponin T (HS-TnT) is a key determinant for presence or absence of acute MI in chest pain patients (pts). Its value for acute MI diagnosis in pts with out-of-hospital cardiac arrest (OHCA) needs assessment because myocardial ischemia may be the cause but also a consequence of cardiac arrest causing global ischemia during no and low flow periods. Methods: Data were prospectively collected. From pts included in the ARREST registry who survived OHCA to discharge with VF as initial rhythm, the cause of OHCA and peak HS-TnT were analyzed. Cause of OHCA was determined independently by researchers, from history, admission and serial ECG, coronary angiography (CAG), cardiac imaging and genetics as available and indicated, without using HS-TnT information. MI diagnosis was made according to the 4 th universal definition of MI: type 1 MI (thrombotic STEMI/NSTEMI), type 2 MI (supply/demand imbalance) and no MI (short transient ECG changes and all non-ischemic causes). Results: From 2012 till 2018 in the study region 373 OHCA pts met the inclusion criteria and had a known peak HS-TnT. Of these, Type 1 MI was present in 109 STEMI and 39 NSTEMI pts, type 2 MI in 116 pts and no MI in 109 pts. No significant coronary stenosis or normal CAG was present in 81 pts: 11/106 (10%) with type 2 MI and 70/109 (64%) without MI. HS-TnT exceeded the conventional diagnostic threshold of 4 times upper limit of normal (4x14ng/L = 56 ng/L) in 99%, 95%, 95% and 89% of pts, respectively. Median peak HS-TnT levels in STEMI, NSTEMI, Type 2 and no AMI pts was 1890 ng/L, 480 ng/L, 300 ng/L and 261 ng/L, respectively. (Figure) Area Under the ROC-Curve of HS-TnT values to differentiate between type 1 NSTEMI and type 2 AMI was 0.649, between type 1 NSTEMI and no MI 0.684 and between type 2 MI and no AMI 0.555. Conclusion: Exclusion of diagnosis of MI in OHCA pts cannot be made with HS-TnT, nor a distinction between NSTEMI, type 2 MI and no AMI. Based on HS-TnT many OHCA pts without ischemic cause would classify as NSTEMI.